Galectin-3 and soluble fibrinogen act in concert to modulate neutrophil activation and survival: involvement of alternative MAPK pathways

Abstract

Galectin-3 (Gal-3), a member of a family of highly conserved carbohydrate-binding proteins, has recently emerged as a novel cellular modulator at inflammatory foci. Here we investigated the effects of Gal-3 on central effector functions of human neutrophils, including phagocytosis, exocytosis of secretory granules, and survival. We examined the effects of Gal-3 alone or in combination with soluble fibrinogen (sFbg), an extracellular mediator that plays a key role during the early phase of the inflammatory response through binding to integrin receptors. In addition we evaluated the intracellular signals triggered by these mediators in human neutrophils. Human neutrophils incubated with recombinant Gal-3 alone increased their phagocytic activity and CD66 surface expression. In contrast to the known antiapoptotic effect of Gal-3 on many cellular types, Gal-3 enhanced PMN apoptotic rate. Preincubation with Gal-3 primed neutrophils to the effects of sFbg, resulting in a synergistic action on degranulation. On the other hand, Gal-3 and sFbg had opposite effects on PMN survival, and the simultaneous action of both agonists partially counteracted the proapoptotic effects of Gal-3. In addition, although sFbg induced its effects through the activation of the ERKs, Gal-3 led to p38 phosphorylation. Disruption of this signaling pathway abrogated Gal-3-mediated modulation of neutrophil degranulation, phagocytosis, and apoptosis. Together, our results support the notion that Gal-3 and sFbg are two physiological mediators present at inflammatory sites that activate different components of the MAPK pathway and could be acting in concert to modulate the functionality and life span of neutrophils.

Differential Roles of Galectin-1 and Galectin-3 in Regulating Leukocyte Viability and Cytokine Secretion

“…Furthermore, only Gal-4 induces nonapoptotic PS exposure independent of intracellular Ca 2ϩ mobilization in neutrophils (26), suggesting the existence of at least two separate pathways regulating nonapoptotic PS exposure. In contrast to the present study, previous results demonstrated that transient treatment of resting neutrophils with Gal-3 enhanced spontaneous apoptosis when analyzed following prolonged incubation (65). However, because high levels of free glycan are unlikely to efficiently disengage Gal-3 once bound to neutrophils, we felt that evaluating the effect of Gal-3 on neutrophil viability and PS exposure following continual treatment with Gal-3 would more appropriately reflect Gal-3 interactions with neutrophils in vivo.…”

A Novel Function for Galectin-1 at the Crossroad of Innate and Adaptive Immunity: Galectin-1 Regulates Monocyte/Macrophage Physiology through a Nonapoptotic ERK-Dependent Pathway

“…It is intriguing that, despite similar carbohydrate specificities, galectins 1 and 3 can trigger different signal transduction pathways on different cell types. In this sense, we have recently demonstrated that galectin-3 induces p38 but not ERK1/2 phosphorylation in human primed neutrophils (48). However, in the present study, we demonstrate that galectin-1 may trigger an ERK1/2-but not p38-dependent signal transduction pathway in human monocytes.…”

Functions of cell surface galectin-glycoprotein lattices

“…Galectin-3-mediated ligand clustering triggers neutrophils to phagocytose, produce reactive oxygen species, release proteases, and secrete interleukin (IL)-8 [15,16,30]. In addition, galectin-3 induces mast cell degranulation: recent studies have revealed a critical role for this protein in mast cell function since galectin-3-deficient mast cells show reduced histamine release and IL-4 secretion [14].…”